Osteoporosis is a metabolic bone disease characterized pathologically by an absolute decrease in the amount of bone, and clinically by increased susceptibility to fractures. Riggs et al., N. Engl. J. Med. (1986), 314:1676; Rusbach et al., in: Textbook of Endocrinology, Ed(s) Williams, (1981), p. 922; Riggs, in: Cecil Textbook of Medicine, Ed(s) Wyngaarden et al., (1985), p. 1456; Riggs et al., Am. J. Med., (1983), 75:899.
There are several biochemical markers which taken together, can be used to either diagnose a patient as osteoporotic, or to study the efficacy of treatments for osteoporosis. For example, urinary hydroxyproline excretion rate is widely used as a marker for bone resorption. Klein et al., Metabolism 2, Vol. 13, No. 3, March 1964, 272-285; Charles et al., J. Clin. Invest., Vol. 76, December 1985 2254-2258; and Deacon et al., Clin. Chim. Acta., 1987, 297-306. Pyridinoline and deoxy-pyridinoline, two types of collagen crosslinks present in bone, which can be detected in urine, are also markers for bone resorption. Robins, et al., European Journal of Clinical Investigation (1991), 21:310-315.
Serum concentrations of osteocalcin serve as a biochemical marker of the rate of bone formation. Osteocalcin is an integral protein of the organic matrix of bone synthesized by bone-forming cells (osteoblasts) during the process of bone formation. A small fraction of the newly synthesized osteocalcin escapes into the circulatory system, thus providing a blood marker of the rate of bone formation. The osteocalcin concentration increases when the bone formation rate increases, and decreases when the bone formation rate decreases. Brown, et al., The Lancet, May 19, 1984, p. 1091, "Serum Bone GLA-Protein: A Specific Marker For Bone Formation in Postmenopausal Osteoporosis". Another reflection of bone resorption/bone formation are changes in calcium and phosphorus balances (positive or negative) which are determined by measuring the difference between the total excretion (feces and urine) and the dietary intake of calcium or phosphorus ion. (These balances are positive when the total excretion is less than the dietary intake.)
Thiazide diuretics are widely used for the treatment of hypertension. In recent years a number of studies have suggested that they may also have a potential role in the prevention of bone loss and osteoporotic fracture, leading to several recent proposals for randomized, controlled clinical trials thereof (Lacroix, Comprehensive Therapy (1991), 17(8): 30-39; Editorial, "Thiazide Diuretics and Osteoporosis", BJCP, Autumn 1991, 45(3); Ray, W. A., Editorial, "Thiazide Diuretics and Osteoporosis: Time for a Clinical Trial?", Jul. 1, 1991, Annals of Internal Medicine 115(1): 64-65).
The proposals that the thiazide diuretics may be effective in the treatment of osteoporosis are based on the recognition that they reduce urinary calcium excretion (Adland-Davenport et al., Am. J. Obstet. Gynecol., (Jul. 15, 1985), 152(6) Part 1: 630-634; Wasnich et al., Obstetrics and Gynecology, (April 1986), 67(4): 457-462; Ray et al., The Lancet, (Apr. 1, 1989): 687-690; Steiniche et al., APMIS, (1989), 97:302-308; and Lacroix et al., New Eng. J. Med., (Feb. 1, 1990): 286-290), improve calcium balance (Wasnich et al., New Eng. J. Med., (Aug. 11, 1983): 344-347; Hunt et al., Am. J. Clin. Nutr., (1989), 50: 517-523; Steiniche et al., 1989; and La Croix et al., 1990) and decrease bone loss (Wasnich et al., Br. Med. J., (1990), 301: 1303-1305), coupled with the recent reported studies associating thiazide use with a decreased risk of hip fracture (Ray et al., 1989; LaCroix et al., 1990; and Felson et al., JAMA, (1991), 265: 370-373).
The thiazide diuretics have, however, been associated with a recognized set of side effects, particularly when administered at higher doses. Administration of the thiazides commonly causes hypokalemia (Bloomfield et al., 1986, J. Clin. Hypertens, 4:331-338; Solomon et al., J. Cardiovasc. Pharmacol. (1991) 17:854-859). They cause postural hypotension, resulting in increased frequency of fainting, dizziness and loss of consciousness in women (La Croix, 1991; Hale et al., J. Am. Geriatric Soc. (1984) 32:5-10). In men, impotence commonly occurs (Papadopoulos, Arch. Intern. Med., Vol. 140, p. 1341 (1980); and Report of Medical Research Council Working Party on Mild to Moderate Hypertension, The Lancet, Sep. 12, 1981, pp. 539-543). In addition, they may adversely affect electrolytes, carbohydrate metabolism, lipids and kidney function (Fried et al., in Diuretics Physiology Pharmacology and Clinical Use, 1986, Chapter 4, pp. 66-82).
It is therefore desirable to take advantage of the hypocalciuric properties of the thiazide diuretics in the treatment of osteoporotic disease, while avoiding the multiple side effects thereof.
U.S. Pat. No. 5,171,583, granted on Dec. 15, 1992, the contents of which are incorporated herein by reference, discloses a method for ameliorating or preventing osteoporosis in humans afflicted with or predisposed to osteoporosis, comprising administering a composition containing a therapeutically or prophylactically-effective amount of a composition of a pharmaceutically-acceptable alkalinizing potassium salt. An effective dose of the alkalinizing potassium salt of 40-400 mmoles/70 kg patient weight/day and preferably 40-250 mmoles/70 kg/day is disclosed therein.
In accordance with the present invention, when the thiazide diuretics are used in combination with the foregoing alkalinizing potassium salts, a method and composition for treating osteoporosis is provided which reduces if not eliminates hypokalemia and the risks and side effects associated with the use of the thiazides.